Biomedical subjects
Publications and source records attributed to J Randerson.
To a maternally transmitted parasite, male hosts are evolutionary prison cells. This is because passage into the next host generation is only possible via egg cytoplasm and not sperm. However, these parasites have come up with a neat array of evolutionary tricks to make the best of their custodial sentence.
AIM: To assess whether p53 gene mutation is important in the pathogenesis and progression of multiple myeloma. METHODS: Thirty eight DNA samples (derived predominantly from bone marrow) obtained from 31 patients with multiple myeloma were examined for mutations in p53 exons 5-9 by polymerase chain reaction single strand conformation polymorphism. Twenty three samples were analysed at the time of diagnosis (one patient had plasma cell leukaemia), three in plateau phase, and 12 at relapse (one plasma cell leukaemia and one extramedullary relapse). RESULTS: One p53 mutation was detected in this group of patients (3.2%). This was seen in the diagnostic bone marrow sample of a 35 year old man with stage IIA disease and occurred in exon 6 as a result of a silent A to G transition at codon 213 (CGA-->CGG), a polymorphism that has been reported in about 3% of breast and lung tumours. CONCLUSIONS: p53 gene mutations are rare events in multiple myeloma and would seem to be of limited value as a prognostic factor.
Twenty-four cases of histologically defined follicle centre cell (FCC) lymphoma have been examined for allele imbalance at 19 microsatellite loci spanning the length of chromosome 6, including six markers within the major histocompatibility complex (MHC), using fluorescent polymerase chain reaction (PCR) to amplify microsatellites. Nineteen cases were observed in which imbalance of one or more markers on chromosome 6 had occurred (79%). The frequency of allele imbalance was significantly higher on 6p than 6q, and two regions of deletions, 6p24-25 and 6p21.3-23, were identified in which the loci showed a significantly high allele imbalance frequency.
Fluorescent polymerase chain reaction (PCR) was used to assay 12 microsatellite markers (APC x 2, DCC, P53 x 2, RB1, NM23, WT1, D6S260, D6S262, D6S281 and TNFa) to look for evidence of microsatellite instability in 40 cases of follicle centre cell lymphoma (FCC). Evidence of novel alleles seen in the tumour tissue but not the normal uninvolved tissue was seen in seven cases (17%). In only two of these cases (5%) was more than one locus involved but in these cases multiple affected loci were seen (4/12 and 7/12 respectively). The detection of microsatellite instability indicates a DNA repair defect such as that which would be predicted to occur in cells with mutated mismatch repair genes, a novel finding in FCC lymphoma.
We have examined 41 cases of follicle centre cell lymphoma with fluorescent PCR of microsatellite repeats closely linked to or within six tumour suppressor gene loci (APC, DCC, P53, RB1, WT1 and NM23). These probes are highly informative with heterozygousity rates in the range of 57%-90%. In addition we have used four loci from chromosome 6 (D6S260, TNFa, D6S281 and D6S262) as control loci which are unlikely to be involved in the pathogenesis of lymphoma. Of 369 informative PCR reactions allele imbalance was identified in 38 (10%) and this was seen in 23 of the 41 cases. Looking at individual loci allele imbalance was seen in APC(1) 11%, APC(2) 12%, P53(1) 5%, P53 (2) 7%, WT1 5%, RB1 13%, DCC 18% and NM23 0%. This frequency of change was no different from that seen at the control loci D6S260 16%, TNFa 20%, D6S281 4% and D6S262 9%. In the indolent phase of germinal centre cell lymphoma there is therefore quite a high rate of allele imbalance at all loci but this is no higher in those loci linked to tumour suppressor genes.
The helicobacter-associated transition from chronic gastritis to MALToma (lymphoma of mucosa-associated lymphoid tissue) may require genetic change in the host. We have studied gastrectomy specimens from twelve cases of primary B-cell gastric lymphoma showing evidence of chronic gastritis and low-grade or high-grade MALToma to look for allele imbalance at microsatellites for six tumour-suppressor genes. We detected allelic imbalance at two of these loci (DCC in three, APC in two). In two DCC cases allele imbalance was seen in the transition from chronic gastritis to low-grade MALToma and in the third between low-grade and high-grade. Allele imbalance between chronic gastritis and low-grade MALToma is not necessarily causal in the transition. Rather, genetic change has occurred in the process of transformation.
Germinal centre cell lymphomas (GCCL) show a wide range of clinical outcomes from persistent indolent disease to large cell transformation. To investigate possible mechanisms of this heterogeneity, a combined morphometric and immunohistological study of p53, bcl-2 and cell proliferation was carried out. There was wide variation in p53 expression between biopsies and between individual follicles in the same tumour. A similar pattern of variation was seen using the cell-cycle marker MIB1, but this did not correlate with p53 expression. Even in cases in which a t(14;18) was demonstrated by PCR, variation occurred in the number of cells expressing bcl-2. On the basis of these results, we suggest that the probability of the clonal expansion of GCCL tumour cells carrying additional genetic abnormalities depends on a complex interaction of cell proliferation with p53 and bcl-2 expression, and that this may account for variation seen in the clinical behaviour seen in this group of tumours.